Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use

• US 6,455,517 B1
• Filed: 07/30/2001
• Issued: 09/24/2002
• Est. Priority Date: 12/24/1997
• Status: Expired due to Term

• Current Assignee: SRI International, Inc.
• Original Assignee: SRI International, Inc.
• Inventors: Tanabe, Masato, Peters, Richard H., Chao, Wan-Ru, Jong, Ling
• Primary Examiner(s): Badio, Barbara P.
• Application Number:
  US09/918,890
• Publication Number:
  US 20020032181A1
• Time in Patent Office: 421 Days
• Field of Search: 514/169, 514/176, 514/182, 552/530, 552/531, 552/558, 540/112
• US Class Current: 514/182
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/04 for inducing labour or abortion; Uterotonics
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/32 Antioestrogens
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07J 41/00 Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
• CPC Class Codes: C07J 41/0072 the A ring of the steroid being aromatic
• CPC Class Codes: C07J 41/0077 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
• CPC Class Codes: C07J 43/003 not condensed

Abstract

Novel anti-estrogenic compounds are provided which are useful to treat a variety of disorders, particularly estrogen-dependent disorders. Preferred compounds have a 1,3,5-estratriene nucleus, and are substituted at the C-17 or C-11 position with a molecular moiety which renders the compounds effective to competitively block the binding of estrogen to its receptor. Particularly preferred compounds are 17-desoxy-1,3,5-estratrienes. Therapeutic methods and pharmaceutical compositions are provided as well.

Claims

1. A method for treating an individual with an estrogen-dependent disorder, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

2. The method of claim 1, wherein the estrogen-dependent disorder is breast cancer.

3. The method of claim 1, wherein the estrogen-dependent disorder is uterine cancer.

4. A method for treating an individual with an non-estrogen dependent cancer, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

5. The method of claim 4, wherein the cancer is multiple drug-resistant.

6. A method for increasing bone mass in the body of a mammalian individual, comprising administering to the individual an effective bone mass increasing amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

7. A method for inhibiting bone loss in the body of a mammalian individual, comprising administering to the individual an effective bone loss inhibiting amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

8. A method for lowering serum cholesterol in the body of a mammalian individual, comprising administering to the individual an effective serum cholesterol lowering amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

9. A method for inhibiting a pulmonary hypertensive disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

10. A method for inhibiting skin atrophy, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

11. A method for inhibiting vaginal atrophy, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

12. A method for inhibiting an estrogen-dependent CNS disorder, comprising prophylatically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteratoms selected from the group containing of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

13. A method for treating osteoporosis in the body of a mammalian individual, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

14. A method for inhibiting a CNS disorder in a postmenopausal human female, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein m is an integer in the range of 1 to 6, p is an integer in the range of 0 to 6, R²⁹ and R³⁰ are independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, and L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.

15. A method for treating an individual with an estrogen-dependent disorder, comprising administering to the individual a therapeutically effective amount of a compound having the structural formula

16. A method for treating an individual with an estrogen-dependent disorder, comprising administering to the individual a therapeutically effective amount of a compound having the structural formula

17. An improved method for transdermally administering a steroid drug having a 1,3,5(10)-estratriene nucleus so that effective blood levels thereof are obtained, the improvement comprising (a) providing the drug in the form of an 11-nitrato derivative;

and (b) delivering the drug to the skin or mucosal tissue in a composition which does not contain a skin permeation enhancer.

18. A method for synthesizing 7α

-methylestrone, comprising contacting an acidic solution of 7α

-methylandrost-4-ene-3,17-dione with CuCl₂.